A damaging or pathological process that disrupts the continuity of axons in the adult mammalian central nervous system (CMS) often results in permanent disability due to the failure of injured axons to regenerate. Current therapeutic interventions are short of eliciting a robust regenerative response that leads to a decent degree of functional recovery. Recently, the emergence of neuronal bridging devices based upon tissue engineering principles offers new hope for the treatment and manipulation of CMS injuries and diseases. By engineering a controlled environment at the lesion site, neural bridging devices awaken the intrinsic ability of CMS axons to regenerate across and beyond the site of injury to reach their appropriate targets. The combined use of material scaffolds containing guidance cues with adhesive molecules and cells of selective properties further confers vitality and resilience to the devices. Our long-term goal is to develop a clinically applicable tissue-engineered neuronal bridging device to repair damaged CNS nerve tracts. The proposed project aims to construct and evaluate a tissue-engineered bridging device based upon a multi-filament entubulation approach in which bundles of ultra-thin filaments are entubulated into a semi- permeable biodegradable hollow fiber membrane sleeve. Our hypothesis is that such a bridging device will convey strong unidirectional guidance cues and define a well-controlled environment for regenerating axons, and therefore promote and guide axonal regeneration following spinal cord injury, leading to a greater degree of functional recovery compared to conventional neuronal bridging strategies. Aim #1 is to evaluate the effect of the packing density of the filament bundles within the HFM entubulation sleeve on the directional outgrowth length and directionality of axons in vitro. Aim #2 is to examine the efficiency of multifilament bridging device in promoting axonal outgrowth using a spinal cord hemisection model in vivo. Aim #3 is to determine whether a combined strategy aimed at 1) enhancing directional regeneration across the lesion gap, and 2) inhibiting glial scar formation at the device-host interface will further promote axonal growth to the lumbar central pattern generator (CPG; an intact neural circuit located within the L1-2 segment that responsible for hindlimb locomotor function), resulting in both anatomical reconnection and functional recovery. [unreadable] [unreadable] [unreadable]